The long term goal is to reline the understanding of the structural basis for the action of hallucinogens on receptors of the neurotransmitter serotonin (5-HT), and to design novel compounds with selective properties as agonists, partial agonists and antagonists on the receptors shared by hallucinogens and other 5-HT-receptor ligands. Such compounds should provide new tools for the investigation of hallucinogens, and offer the promise for new therapeutic and preventive modalities. The proposal focuses on the 5-HT1A and 5-HT2 receptors. A molecular model for pharmacological drug efficacy at 5-HT1A receptors was developed from specific molecular mechanisms of receptor recognition and activation. It will be calibrated and refined using stimulations of a large chemical variety of known an d putative 5-HT1A ligands positioned inside a model receptor protein identified in preliminary studies. Effects of ligands on the receptor activation mechanism (proton transfer) will be evaluated with the computational methods of quantum chemistry and molecular dynamics (MD). Results will be used to define molecular correlates of efficacy which will serve in the design of new molecular structures with selectivity for 5-HT1A receptors and predicted degrees of agonistic activity. The validity and applicability of the correlates will be probed theoretically as well as experimentally (see below). Following similar protocols, the elements of recognition and activation at 5-HT2 receptors will be defined based on the working hypothesis that the interaction of drugs at this receptor is governed by stacking with a residue of an aromatic amino acid. Short peptide sequences (e.g., Arg-Phe-Ser-Trp, Trp-Ser-Tyr, Phe-Arg-Trp) from proteins known to bind 5-HT, including myelin basic protein, LHRH and MSH- ACTH will serve as first models of targets for 5-HT2 selective ligands. The relationship between conclusions based on the model receptor proteins for both the 5-HT1A and the 5-HT2 receptors, and mechanisms involving the real 5HT-receptors, will be probed against inferences from the amino acid sequences of he authentic receptor proteins. Experimentally determined pharmacological profiles of compounds acting at the two 5-HT receptors will be used to establish the relation between molecular structure and drug efficacy. Compounds in the chemical classes represented by derivatives of indole, phenylalkylamine and ergoline, will be studied in these systems in comparison with known agonists and antagonists on the receptors. Assays will include: a) responses mediated by the 5-HT1A receptor coupled to adenylate cyclase i membrane preparations from rat hippocampus, and b) the contraction of the isolated rabbit aorta mediated by 5-HT2 receptors; independent measures of drug efficacy will be obtained. Changes in efficacy as function of concentration of the Ca2+ activator BAY K 8644 which converts an apparent antagonist, d-LSD, to a 5-HT2 agonist with low efficacy, and those resulting will also be evaluated. The modulation of agonist binding in human and rat brain sections by receptor-G protein interactions will be studied from autoradiography experiments.